Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenetic alopecia which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyper-androgenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Non-steroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethylisobuty-ranilide. See Neri., et al., Endocrinol. 1972, 91 (2). However, these products, though devoid of hormonal effects, compete with all natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host and/or initiate feed-back effects which would cause hyperstimulation of the testes.
The principal mediator of androgenic activity in some target organs, e.g., the prostate, is 5.alpha.-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of testosterone-5.alpha.-reductase (or simply 5.alpha.-reductase). Inhibitors of 5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. Nos. 4,377,584, issued Mar. 22, 1983, and 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that a second 5.alpha.-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (Nov. 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5.alpha.-reductase 1 (or 5.alpha.-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5.alpha.-reductase 2 (or 5.alpha.-reductase type 2).
In the treatment of androgenic sensitive disease conditions, e.g., benign prostatic hyperplasia (BPH) and treatment of prostatic cancer, it would be desirable to have one drug entity which is active against both isozymes in the prostate to significantly inhibit all dihydrotestosterone production. It would also be desirable to have another drug entity which is highly selective for inhibiting the isozyme 5.alpha.-reductase 1 associated with the scalp, for use in treating conditions of the skin and scalp, e.g., acne vulgaris, male pattern baldness and hirsutism in females. Additionally, a selective 5.alpha.-reductase 1 inhibitor could be used in combination with a 5.alpha.-reductase 2 inhibitor such as, e.g., finasteride (PROSCAR.RTM.), for therapy in the treatment of hyperandrogenic conditions such as BPH and treatment of prostatic cancer, and for the treatment of skin and scalp-related disorders such as acne vulgaris, seborrhea, female hirsutism, and androgenic alopecia. Still further, the 5.alpha.-reductase 1 inhibitors of this invention could be used in combination with a potassium channel opener such as minoxidil for the treatment of these skin and scalp-related disorders. Therefore it is an object of this invention to provide compounds that have sufficient activity in the inhibition of 5.alpha.-reductase isozyme 1.